The quantitative determination of analytes in biological fluids is important in the diagnosis and maintenance of certain physiological abnormalities. For example, lactate, cholesterol, and bilirubin should be monitored in certain individuals. In particular, determining glucose concentrations in biological fluids is important to diabetic individuals who must regulate the glucose intake of their diets. The results of such tests may be used to determine what, if any, insulin or other medication should be administered.
In some existing technologies, a lancet is used to pierce a user's skin to draw a biological fluid sample, such as blood. This sample is then analyzed with a test sensor external to the skin to determine the concentration of analyte, such as glucose, in the sample. Piercing a user's skin each time an analyte concentration reading is desired is an inconvenient and invasive procedure. Moreover, the procedure is undesirable due to the pain and discomfort experienced by the user.
In other existing technologies, an implant, as described in U.S. Pat. No. 5,517,313 may be placed under the skin. In addition to patient discomfort from the implant placement procedure and healing process, immune system responses may affect the usefulness of the implant differently for individual patients. Thus, implantable sensors may not be useful for some patients.
Conventional non-invasive methods for obtaining a biological fluid sample typically involve extracting a sample of interstitial fluid (ISF) containing the analyte to the surface of the skin for analysis. Transport of the ISF may be accomplished electrically through iontophoresis or by enlarging and/or creating pores through the stratum corneum of the skin. As the sample moves from the epidermal layer of the skin, through the stratum corneum, and to the skin surface, such methods may be referred to as “transdermal.” Transdermal methods may be preferred to invasive methods, as patient discomfort and immune system complications are substantially reduced. Transdermal methods also include techniques in which the sample moves through tissues other than skin, such as mucosal tissues, to reach the test sensor.
In transdermal systems relying on iontophoresis, electricity flowing between a pair of electrodes transports ISF to the skin surface for analysis. An example of a transdermal iontophoresis system may be found in U.S. Pat. No. 6,393,318. A commercial transdermal system based on iontophoresis was the GlucoWatch® G2 Biographer (Animas® Corporation; West Chester, Pa.). A disadvantage of iontophoretic sensor systems is that the user's skin may be irritated by the current flowing between the electrodes.
In poration or microporation transdermal methods, small holes or pores are made through the stratum corneum of the skin to a desired depth to lessen the barrier properties of the skin to the passage of biological fluids, such as ISF. Preferably, such pores are about 1 mm or less in average diameter. A transdermal test sensor placed on the surface of the user's porated skin receives the fluid from the pores. Sonication, tiny needles, and other methods are known to porate the skin, thereby enhancing fluid flow to the surface of the skin.
When the fluid reaches the skin surface, it is typically trapped by the reservoir and/or absorptive material of the transdermal test sensor. The test sensor may include a hydrogel or other aqueous material to facilitate the extraction of the fluid from the user's skin to the electrodes of the test sensor. Conventional transdermal electrochemical test sensor designs relying on hydrogels, such as the sensor of the GlucoWatch® system, have disadvantages including interference and delayed diffusion of by-products to the electrode surface caused by the viscosity of the hydrogel, relatively long delays between application of the hydrogel to the skin and useful analysis, relatively high levels of background signal, as well as contamination complications resulting from diffusion of hydrogen peroxide to the electrodes.
The measurement performance of a biosensor system, such as a transdermal sensor system, typically is defined in terms of accuracy and/or precision. Accuracy may be expressed in terms of bias of the sensor system's analyte reading in comparison to a reference analyte reading, with larger bias values representing less accuracy. Precision may be expressed in terms of the spread or variance of the bias among multiple analyte readings in relation to a mean. It would be desirable to increase the accuracy and/or precision of transdermal sensor systems, to provide for an improvement in measurement performance.
Bias is the difference between one or more analyte concentration values determined from the biosensor system, and one or more accepted reference values for the analyte concentration in the biological fluid. Thus, one or more errors of a biosensor system in its analysis can result in a bias of the analyte concentration determined from the system. Bias may be expressed in terms of “absolute bias” in the units of the measurement such as mg/dL, or in terms of “percent bias” as a percentage of the absolute bias value over the reference value. Under the ISO standard for glucose measurements, absolute bias is used to express error in glucose concentrations less than 75 mg/dL, while percent bias is used to express error in glucose concentrations of 75 mg/dL and higher. Accepted reference values for analyte concentrations may be obtained with a reference instrument, such as the YSI 2300 STAT PLUS™ available from YSI Inc., Yellow Springs, Ohio.
Accordingly, it would be desirable to have a transdermal sensor system that assists in addressing one or more of the above disadvantages.